1. Field of the Invention
The present invention relates to the novel design and synthesis of disubstituted or deoxydisubstituted .alpha.-D-mannofuranosides and .beta.-L-gulofuranosides and intermediates for preparing these disubstituted derivatives. More specifically, this invention relates to alkyl or aralkyl 2,3-O-(1-methylethylidene)-.alpha.-D-mannofuranoside and .beta.-L-gulofuranoside derivatives substituted at 1,5 or 1,6 - positions. It also relates to deoxy-hexofuranoside compounds wherein the chirality at position 5 is completely inverted. The compounds of this invention have anti-inflammatory and anti-proliferative activity and are useful for treating warm blooded animals and mammals with rheumatoid arthritis, osteoarthritis, scleroderma, systematic lupus erythematosus, autoimmune deficiency syndrome, atopic dermatitis, psoriasis and cancer. This invention also encompasses pharmaceutical compositions containing these disubstituted or deoxydisubstituted compounds and methods of treating inflammatory and/or autoimmune disorders.
2. Description of the Related Art
A glycoside is formed when the hydrogen atom of an anomeric hydroxyl group is replaced by a substituted or unsubstituted carbon atom. Typically, glycosides are formed either for group protection or as a part of a synthesis of a larger molecule. The Fischer method is particularly effective for synthesizing glycosides from unprotected reducing sugars and low molecular weight alcohols. Normally, after the glycoside is formed, various blocking methods are used to block or protect one or more of the hydroxyl groups. These blocking methods are described in U.S. Pat. Nos. 2,715,121, 4,056,322, 4,735,934, 4,996,195, and 5,010,058 the disclosure of which are incorporated herein by reference. The therapeutic activity of hexoses and their derivatives are also disclosed in the above application.
A well known derivative of .alpha.-D-glucose having beneficial therapeutic properties is Amiprilose HCl, 1,2-O-isopropylidene-3-O-3'-(N', N'-dimethylaminopropyl)-.alpha.-D-glucofuranose. This compound, which is in the late Phase III clinical trials, has anti-inflammatory activity and demonstrated utility in managing the signs and symptoms of rheumatoid arthritis. More generally, these type of compounds have activity as immunomodulators, and therefore have a therapeutic effect on other autoimmune disorders such as psoriasis, eczema, or lupus (U.S. Pat. No. 5,010,058).
Unfortunately, while some of the prior art monosaccharide derivatives have shown beneficial therapeutic activity, high doses of these compounds, such as Amiprilose HCl, are often needed to be effective and produce the desired results. Therefore, the prior art derivatives are difficult to prescribe orally. Because therapy for inflammatory and autoimmune disorders is often midterm or longterm, there is a need to develop potent, non-toxic compounds which can be orally administered to promote ease of treatment and patient compliance.